Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEP4I5O)

• DOT Name: NAD(+) hydrolase SARM1 (SARM1)
• Synonyms: NADase SARM1; hSARM1; EC 3.2.2.6; NADP(+) hydrolase SARM1; EC 3.2.2.-; Sterile alpha and Armadillo repeat protein; Sterile alpha and TIR motif-containing protein 1; Sterile alpha motif domain-containing protein 2; MyD88-5; SAM domain-containing protein 2; Tir-1 homolog; HsTIR
• Gene Name: SARM1
• Related Disease:
  Amyotrophic lateral sclerosis
  Nervous system disease
  Fatty liver disease
  Gastric cancer
  Late-onset Parkinson disease
  Metabolic disorder
  Motor neurone disease
  Non-alcoholic fatty liver disease
  Parkinson disease
  Peripheral neuropathy
  Prion disease
  Prostate cancer
  Prostate carcinoma
  Respiratory syncytial virus infection
  Stomach cancer
  Chronic obstructive pulmonary disease
  Amyotrophic lateral sclerosis type 1
  Frontotemporal dementia
• UniProt ID: SARM1_HUMAN
• PDB ID: 6O0Q ; 6O0R ; 6O0S ; 6O0T ; 6O0U ; 6O0V ; 6O1B ; 6QWV ; 6WPK ; 6ZFX ; 6ZG0 ; 6ZG1 ; 7ANW ; 7CM5 ; 7CM6 ; 7CM7 ; 7DJT ; 7KNQ ; 7LD0 ; 7NAG ; 7NAH ; 7NAI ; 7NAJ ; 7NAK ; 7NAL ; 7QG0 ; 8D0C ; 8D0D ; 8D0E ; 8D0F ; 8D0G ; 8D0H ; 8D0I ; 8D0J ; 8GNI ; 8GNJ ; 8GQ5 ; 8P2L
• EC Number: 3.2.2.-; 3.2.2.6
• Pfam ID: PF07647 ; PF13676
• Sequence:
  MVLTLLLSAYKLCRFFAMSGPRPGAERLAVPGPDGGGGTGPWWAAGGRGPREVSPGAGTE
  VQDALERALPELQQALSALKQAGGARAVGAGLAEVFQLVEEAWLLPAVGREVAQGLCDAI
  RLDGGLDLLLRLLQAPELETRVQAARLLEQILVAENRDRVARIGLGVILNLAKEREPVEL
  ARSVAGILEHMFKHSEETCQRLVAAGGLDAVLYWCRRTDPALLRHCALALGNCALHGGQA
  VQRRMVEKRAAEWLFPLAFSKEDELLRLHACLAVAVLATNKEVEREVERSGTLALVEPLV
  ASLDPGRFARCLVDASDTSQGRGPDDLQRLVPLLDSNRLEAQCIGAFYLCAEAAIKSLQG
  KTKVFSDIGAIQSLKRLVSYSTNGTKSALAKRALRLLGEEVPRPILPSVPSWKEAEVQTW
  LQQIGFSKYCESFREQQVDGDLLLRLTEEELQTDLGMKSGITRKRFFRELTELKTFANYS
  TCDRSNLADWLGSLDPRFRQYTYGLVSCGLDRSLLHRVSEQQLLEDCGIHLGVHRARILT
  AAREMLHSPLPCTGGKPSGDTPDVFISYRRNSGSQLASLLKVHLQLHGFSVFIDVEKLEA
  GKFEDKLIQSVMGARNFVLVLSPGALDKCMQDHDCKDWVHKEIVTALSCGKNIVPIIDGF
  EWPEPQVLPEDMQAVLTFNGIKWSHEYQEATIEKIIRFLQGRSSRDSSAGSDTSLEGAAP
  MGPT
• Function: NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism. Acts as a negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway by promoting Wallerian degeneration, an injury-induced form of programmed subcellular death which involves degeneration of an axon distal to the injury site. Wallerian degeneration is triggered by NAD(+) depletion: in response to injury, SARM1 is activated and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR (cADPR) and nicotinamide; NAD(+) cleavage promoting cytoskeletal degradation and axon destruction. Also able to hydrolyze NADP(+), but not other NAD(+)-related molecules. Can activate neuronal cell death in response to stress. Regulates dendritic arborization through the MAPK4-JNK pathway. Involved in innate immune response: inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38.
• Tissue Specificity: Predominantly expressed in brain, kidney and liver. Expressed at lower level in placenta.
• KEGG Pathway: Nicoti.te and nicoti.mide metabolism (hsa00760)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis	DISF7HVM	Definitive	Biomarker	[1]
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[2]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Late-onset Parkinson disease	DIS9IOUI	Strong	Altered Expression	[5]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[3]
Motor neurone disease	DISUHWUI	Strong	Altered Expression	[6]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[3]
Parkinson disease	DISQVHKL	Strong	Posttranslational Modification	[5]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[7]
Prion disease	DISOUMB0	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[9]
Respiratory syncytial virus infection	DIS7FWHY	Strong	Biomarker	[10]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[11]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Limited	Genetic Variation	[12]
Frontotemporal dementia	DISKYHXL	Limited	Biomarker	[1]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NAD(+) hydrolase SARM1 (SARM1).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of NAD(+) hydrolase SARM1 (SARM1).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of NAD(+) hydrolase SARM1 (SARM1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of NAD(+) hydrolase SARM1 (SARM1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NAD(+) hydrolase SARM1 (SARM1).	[18]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NAD(+) hydrolase SARM1 (SARM1).	[17]

References

• [1] Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss.Acta Neuropathol Commun. 2019 Oct 28;7(1):166. doi: 10.1186/s40478-019-0800-9.
• [2] Gene therapy targeting SARM1 blocks pathological axon degeneration in mice.J Exp Med. 2019 Feb 4;216(2):294-303. doi: 10.1084/jem.20181040. Epub 2019 Jan 14.
• [3] SARM1 deletion restrains NAFLD induced by high fat diet (HFD) through reducing inflammation, oxidative stress and lipid accumulation.Biochem Biophys Res Commun. 2018 Apr 6;498(3):416-423. doi: 10.1016/j.bbrc.2018.02.115. Epub 2018 Feb 15.
• [4] Cancer-associated fibroblasts promote malignancy of gastric cancer cells via Nodal signalling.Cell Biochem Funct. 2020 Jan;38(1):4-11. doi: 10.1002/cbf.3446. Epub 2019 Nov 16.
• [5] c-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD(+) cleavage activity to inhibit mitochondrial respiration.J Biol Chem. 2018 Dec 7;293(49):18933-18943. doi: 10.1074/jbc.RA118.004578. Epub 2018 Oct 17.
• [6] SARM: From immune regulator to cell executioner.Biochem Pharmacol. 2019 Mar;161:52-62. doi: 10.1016/j.bcp.2019.01.005. Epub 2019 Jan 8.
• [7] Emergence of SARM1 as a Potential Therapeutic Target for Wallerian-type Diseases.Cell Chem Biol. 2020 Jan 16;27(1):1-13. doi: 10.1016/j.chembiol.2019.11.002. Epub 2019 Nov 21.
• [8] SARM1 deficiency up-regulates XAF1, promotes neuronal apoptosis, and accelerates prion disease.J Exp Med. 2019 Apr 1;216(4):743-756. doi: 10.1084/jem.20171885. Epub 2019 Mar 6.
• [9] HOX genes: Major actors in resistance to selective endocrine response modifiers.Biochim Biophys Acta. 2016 Apr;1865(2):105-10. doi: 10.1016/j.bbcan.2016.01.003. Epub 2016 Jan 22.
• [10] Resveratrol inhibits the TRIF-dependent pathway by upregulating sterile alpha and armadillo motif protein, contributing to anti-inflammatory effects after respiratory syncytial virus infection.J Virol. 2014 Apr;88(8):4229-36. doi: 10.1128/JVI.03637-13. Epub 2014 Jan 29.
• [11] SARCOPENIA: AN ENDOCRINE DISORDER?.Endocr Pract. 2017 Sep;23(9):1140-1149. doi: 10.4158/EP171795.RA. Epub 2017 Jul 13.
• [12] Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis.Nat Commun. 2017 Sep 20;8(1):611. doi: 10.1038/s41467-017-00471-1.
• [13] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.